PROTEOGLYCANS IN GROWTH FACTOR SIGNALING AND DEVELOPMENT

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DESCRIPTION (PROVIDED BY APPLICANT): Cell surface proteoglycans serve critical functions in the tissue-selective regulation of growth factor signaling. Current evidence indicates that proteoglycans control the assembly of growth factor ligand-receptor complexes at the cell surface. Glypicans represent one family of integral membrane proteoglycans, characterized by a GPIlinkage to the outer leaflet of the plasma membrane and heparan sulfate modification. One human glypican, GPC3, is remarkable for its role in the regulation of body size and tumor development. Glypicans are also widely expressed in the vertebrate nervous system, although nothing is known about their function in this tissue. The long term goals of this project are to understand the diverse molecular functions of glypicans, including their involvement in growth control, tumor suppression, and nervous system development using genetic and molecular tools available in the fruitfly, Drosophila melanogaster. We have identified mutations affecting both of the two glypican encoding genes in Drosophila, division abnormally delayed (daily), and daily-like (dly). Our recent studies have shown that daily and daily-like affect tissue and cell growth at least in part by regulation of Insulin-like growth factor signaling. We have also uncovered axonogenesis defects in the central nervous system of dly mutants. Finally, we have determined that glycosaminoglycan biosynthesis is critical for assembly of the neuromuscular synapse in Drosophila. These observations serve as the basis of our specific aims: Aim 1. Determine the molecular activity of daily and daily-like in cell and tissue growth control. Aim 2. Examine the molecular mechanisms of Daily and Daily-like mediated inhibition of insulin responses in Drosophila S2 cells. Aim 3. Determine the molecular and cellular basis of embryonic axon projection defects in daily-like mutants. Aim 4. Establish the molecular basis for glypican and glycosaminoglycan function in synapse assembly.